Large granular lymphocytic leukemia explained

Large granular lymphocytic leukemia
Field:Hematology, oncology

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.[1]

It is divided in two main categories: T-cell LGL leukemia (T-LGLL) and natural-killer (NK)-cell LGL leukemia (NK-LGLL). As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).[2]

In a study based in the US, the average age of diagnosis was 66.5 years[3] whereas in a French study the median age at diagnosis was 59 years (with an age range of 12–87 years old). In the French study, only 26% of patients were younger than 50 years which suggests that this disorder is associated with older age at diagnosis. Due to lack of presenting symptoms, the disorder is likely to be underdiagnosed in the general population.[4]

Signs and symptoms

This disease is known for an indolent clinical course and incidental discovery.[1] The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to anaemia and/or neutropenia[5] are seen in almost half of cases.[6] [7] [8] [9]

Rheumatoid arthritis is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome.[10] Signs and symptoms of anemia are commonly found, due to the association between T-LGLL and erythroid hypoplasia.[11]

Sites of involvement

The leukemic cells of T-LGLL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.[1] [6]

Cause

The postulated cells of origin of T-LGLL leukemia are transformed CD8+ T-cell with clonal rearrangements of β chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of γ chain T-cell receptor genes for a minority of cases.[1]

Diagnosis

Laboratory findings

The requisite lymphocytosis of this disease is typically 2-20x109/L.[11]

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.[9] [12] [13] [14]

Peripheral blood

The neoplastic lymphocytes seen in this disease are large in size with azurophilic granules that contains proteins involved in cell lysis such as perforin and granzyme B.[15] Flow cytometry is also commonly used.[16]

Bone marrow

Bone marrow involvement in this disease is often present, but to a variable extent. Bone marrow biopsy is commonly used for diagnosis. The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs.[1]

Immunophenotype

The neoplastic cells of this disease display a mature T-cell immunophenotype, with the majority of cases showing a CD4-/CD8+ T-cell subset immunophenotype versus other permutations of those markers.[7] [8] Variable expression of CD11b, CD56, and CD57[9] are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.[1]

Type Immunophenotype
Common type (80% of cases)CD3+, TCRαβ+, CD4-, CD8+
Rare variantsCD3+, TCRαβ+, CD4+, CD8-
CD3+, TCRαβ+, CD4+, CD8+
CD3+, TCRγδ+, CD4 and CD8 variable

Genetic findings

Clonal rearrangements of the T-cell receptor (TCR) genes are a necessary condition for the diagnosis of this disease. The gene for the β chain of the TCR is found to be rearranged more often than the γ chain. of the TCR.[13] [17]

Current evidence suggests that patients with STAT3 mutations are more likely to respond to methotrexate therapy.[18]

Treatment

First line treatment is immunosuppressive therapy. A weekly dosage of Methotrexate (with or without daily Prednisone) may induce partial or complete response in some patients while others may require Cyclosporine or Cyclophosphamide.[5]

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.[19]

Experimental data suggests that treatment with calcitrol (the active form of vitamin D) may be useful in treating T-cell LGL due to its ability to decrease pro-inflammatory cytokines.[20]

Prognosis

The 5 year survival has been noted as 89% in at least one study from France of 201 patients with T-LGL leukemia.[21]

Epidemiology

T-LGLL is a rare form of leukemia, comprising 2-3% of all cases of chronic lymphoproliferative disorders.

History

LGLL was discovered in 1985 by Thomas P. Loughran Jr. while working at Fred Hutchinson Cancer Research Center.[22] Specimens from patients with LGLL are banked at the University of Virginia for research purposes, the only bank for such purposes.[23]

Notes and References

  1. Book: Elaine Sarkin Jaffe . Nancy Lee Harris . World Health Organization . International Agency for Research on Cancer . Harald Stein . J.W. Vardiman . Pathology and genetics of tumours of haematopoietic and lymphoid tissues . IARC Press . Lyon . 2001 . World Health Organization Classification of Tumors . 3 . 978-92-832-2411-2 .
  2. Epling-Burnette PK, Sokol L, Chen X, et al. . Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling . Blood . 112 . 12 . 4694–8 . December 2008 . 18791165 . 10.1182/blood-2008-02-136382 . 2597136.
  3. Shah. M V. Hook. C C. Call. T G. Go. R S. August 2016. A population-based study of large granular lymphocyte leukemia. Blood Cancer Journal. En. 6. 8. e455. 10.1038/bcj.2016.59. 2044-5385. 5022177. 27494824.
  4. Kojić Katović. Sandra. 2018. T-Cell Large Granular Lymphocytic Leukemia – Case Report. Acta Clinica Croatica. en. 57. 2. 362–365. 10.20471/acc.2018.57.02.18. 30431731. 6531996. 0353-9466.
  5. Sanikommu. Srinivasa R.. Clemente. Michael J.. Chomczynski. Peter. Afable. Manuel G.. Jerez. Andres. Thota. Swapna. Patel. Bhumika. Hirsch. Cassandra. Nazha. Aziz. 2017-06-20. Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL). Leukemia & Lymphoma. en. 59. 2. 416–422. 10.1080/10428194.2017.1339880. 28633612. 8694069 . 1042-8194.
  6. Large Granular Lymphocyte Leukemia . Cancer Control . 5 . 1 . 25–33 . January 1998 . 10761014 . 10.1177/107327489800500103 . Lamy T, Loughran TP .
  7. Chan WC, Link S, Mawle A, Check I, Brynes RK, Winton EF . Heterogeneity of large granular lymphocyte proliferations: delineation of two major subtypes . Blood . 68 . 5 . 1142–53 . November 1986 . 10.1182/blood.V68.5.1142.1142 . 3490288 . free .
  8. Pandolfi F, Loughran TP, Starkebaum G, et al. . Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes. A multicenter study . Cancer . 65 . 2 . 341–8 . January 1990 . 2403836 . 10.1002/1097-0142(19900115)65:2<341::AID-CNCR2820650227>3.0.CO;2-2. free .
  9. Lamy T. vanc. Clinical features of large granular lymphocyte leukemia . Semin. Hematol. . 40 . 3 . 185–95 . July 2003 . 12876667 . 10.1016/S0037-1963(03)00133-1. Loughran . TP .
  10. Loughran TP, Starkebaum G, Kidd P, Neiman P . Clonal proliferation of large granular lymphocytes in rheumatoid arthritis . Arthritis Rheum. . 31 . 1 . 31–6 . January 1988 . 3345230 . 10.1002/art.1780310105.
  11. Kwong YL, Wong KF . Association of pure red cell aplasia with T large granular lymphocyte leukaemia . J. Clin. Pathol. . 51 . 9 . 672–5 . September 1998 . 9930071 . 500904 . 10.1136/jcp.51.9.672.
  12. Oshimi K, Yamada O, Kaneko T, et al. . Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders . Leukemia . 7 . 6 . 782–8 . June 1993 . 8388971 .
  13. Loughran TP, Starkebaum G, Aprile JA . Rearrangement and expression of T-cell receptor genes in large granular lymphocyte leukemia . Blood . 71 . 3 . 822–4 . March 1988 . 10.1182/blood.V71.3.822.822 . 3345349 . free .
  14. Loughran TP, Kadin ME, Starkebaum G, et al. . Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia . Ann. Intern. Med. . 102 . 2 . 169–75 . February 1985 . 3966754 . 10.7326/0003-4819-102-2-169.
  15. Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP . The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis . Blood . 89 . 1 . 256–60 . January 1997 . 10.1182/blood.V89.1.256 . 8978299 .
  16. Lamy. Thierry. Loughran. Thomas P.. 2011-03-10. How I treat LGL leukemia. Blood. en. 117. 10. 2764–2774. 10.1182/blood-2010-07-296962. 0006-4971. 3062292. 21190991.
  17. Vie H, Chevalier S, Garand R, et al. . Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder . Blood . 74 . 1 . 285–90 . July 1989 . 10.1182/blood.V74.1.285.285 . 2546620 . free .
  18. Shi. Min. He. Rong. Feldman. Andrew L.. Viswanatha. David S.. Jevremovic. Dragan. Chen. Dong. Morice. William G.. March 2018. STAT3 mutation and its clinical and histopathologic correlation in T-cell large granular lymphocytic leukemia. Human Pathology. 73. 74–81. 10.1016/j.humpath.2017.12.014. 29288042. 0046-8177.
  19. Rosenblum MD, LaBelle JL, Chang CC, Margolis DA, Schauer DW, Vesole DH . Efficacy of alemtuzumab treatment for refractory T-cell large granular lymphocytic leukemia . Blood . 103 . 5 . 1969–71 . March 2004 . 14976065 . 10.1182/blood-2003-11-3951 . free .
  20. Olson. Kristine C.. Kulling. Paige M.. Olson. Thomas L.. Tan. Su-Fern. Rainbow. Rebecca J.. Feith. David J.. Loughran. Thomas P.. 2016-10-07. Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia. Cancer Biology & Therapy. en. 18. 5. 290–303. 10.1080/15384047.2016.1235669. 1538-4047. 5499847. 27715403.
  21. 2930955. Analysis of a French cohort of patients with large granular lymphocyte leukemia: A report on 229 cases. 2010. 95. 9. 20378561. Bareau. B. Rey. J. Hamidou. M. Donadieu. J. Morcet. J. Reman. O. Schleinitz. N. Tournilhac. O. Roussel. M. Fest. T.. Lamy. T.. 1534–41. 10.3324/haematol.2009.018481. Haematologica. 8.
  22. Web site: Archived copy . 2016-12-12 . 2016-12-21 . https://web.archive.org/web/20161221061035/https://cancer.uvahealth.com/LGLLeBookNew.pdf . dead .
  23. Web site: LGL Leukemia Program | UVA Health System.

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